Enantioselective addition of organometallics to aldehydes using camphor derived chiral 1,4-aminoalcohols as ligands

Article abstract of DOI:10.1016/S0957-4166(99)00413-9

(+)-Camphor derived enantiomerically pure 1,4-aminoalcohols have been used as ligands in the addition reactions of n-BuLi and n-BuMgBr to benzaldehyde and in the reaction of diethylzinc with benzaldehyde and hexanal. All chiral secondary alcohols were obt

Full text of DOI:10.1016/S0957-4166(99)00413-9

Pergamon
Tetrahedron: Asymmetry 10 (1999) 3969–3975
Enantioselective addition of organometallics to aldehydes using
camphor derived chiral 1,4-aminoalcohols as ligands
Max Knollmüller,∗ Mathias Ferencic and Peter Gärtner
Institute of Organic Chemistry, Vienna University of Technology, Getreidemarkt 9, A-1060 Vienna, Austria
Received 19 August 1999; accepted 15 September 1999
Abstract
(+)-Camphor derived enantiomerically pure 1,4-aminoalcohols have been used as ligands in the addition
reactions of n-BuLi and n-BuMgBr to benzaldehyde and in the reaction of diethylzinc with benzaldehyde and
hexanal. All chiral secondary alcohols were obtained in good chemical yields and enantioselectivities were up to
87% ee in the addition of diethylzinc. © 1999 Elsevier Science Ltd. All rights reserved.
1. Introduction
One of the most important and fundamental synthetic procedures to establish a new carbon–carbon
bond stereoselectively is the enantioselective addition of organometallic reagents to aldehydes affording
chiral secondary alcohols.1,2 This structural feature is part of many natural products or can serve as
an important synthetic intermediate for various other functionalities, e.g. halide, amine, ester and ether,
and is therefore a valuable target. A frequently used method to achieve this enantioselective addition
is to perform the reaction in the presence of a chiral ligand such as an aminoalcohol.3–5 Many chiral
ligands have already been synthesized and tested in this type of reaction; however, mostly ligands with
1,2-functionalities have been used.6 Besides a few examples7–9 demonstrating the efficient use of γ-
aminoalcohols, the synthesis and utilization of (+)-camphor and (−)-menthone derived 1,4-aminoalcohols
as ligands for diethylzinc have been reported.10–12 Recently, we described the synthesis of seven new 1,4-
aminoalcohols 2a–g from lactone 1 by a simple two-step procedure (Scheme 1).13
In the present communication, results of the application of 2a–g as chiral additives in the reaction of
different organometallic reagents with benzaldehyde and hexanal are reported (Scheme 2).
∗
Corresponding author. Fax: +43-1-58801-154 92; e-mail: mknollmu@mail.zserv.tuwien.ac.at
0957-4166/99/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(99)00413-9

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Scheme 1. Synthesis of the 1,4-aminoalcohols 2a–g
Scheme 2. Selectivity experiments with the 1,4-aminoalcohols 2a–g as chiral additives
2. Results and discussion
With alkyllithium and Grignard compounds being the most readily available and widely used organo-
metallic reagents, we decided to test our ligands with these systems first. In this area many examples14,15
have been described so far. Only recently, successful applications of 1,2-aminoalcohols as ligands for
RLi16 and the use of 1,4-diols of the TADDOL-type for RMgBr17 have been reported.
The reactions with butylmagnesium bromide and butyllithium were carried out in diethylether as well
as in tetrahydrofuran, because it is known that these solvents form complexes with the organometallic
reagent and in earlier investigations18 we have observed a strong influence of the solvent on the
enantioselectivity. For reasons of comparability and to exclude any reaction of an organometallic species
without a chiral ligand we chose the same reaction conditions as described earlier.18 Thus, since one
equivalent of the organometallic reagent is consumed by deprotonating the secondary hydroxy group of
the ligand, the reaction was carried out using 3:organometallic reagent:1 in a molar ratio of 1:9.2:5.2 at a

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Table 1
Enantiomeric excesses of 1-phenyl-1-pentanol 9 in the alkylation of benzaldehyde 3 by n-BuLi 6 and
n-BuMgBr 7 in the presence of the aminoalcohols 2a–g
reaction temperature of −78°C. Due to the low temperature we had to accept that with some ligands the
reaction mixtures were heterogeneous. But this fact should not have any fundamental influence on the
results, because even in heterogeneous systems high selectivities can be achieved.15c
The results in Table 1 show that the enantioselectivities we obtained with our 1,4-aminoalcohols were
only moderate (up to 37% ee), with no significance with regard to the solvent or the configuration of the
preferably formed enantiomer. Thus, we changed the organometallic reagent to investigate the application
of 2a–g in the addition reaction of diethylzinc to aldehydes.19 Because it is known that most of the
catalysts reported are highly effective for aromatic and α-branched aliphatic aldehydes, we did our first
experiments in this series with benzaldehyde 3 (cf. lit.,1 pp. 1298–1299). Additionally, we were especially
interested in testing the best of our reagent–ligand systems for an unhindered aliphatic aldehyde, for
which only limited success has been achieved so far.20–23 As a representative example of this group we
chose the addition of diethylzinc to hexanal 5. The reaction was carried out by the addition of 2 equiv. of
8 to 3 in the presence of 0.1 equiv. of the catalyst 2a–g in toluene. For the experiments giving best results
(yield 94%, 87% ee), the amount of aminoalcohol was reduced to 0.05 and 0.02 equiv., respectively,
without affecting either the conversion or the enantioselectivity significantly. Only if the reaction was
carried out with the best of our ligands 2g at −30°C was the reaction rate reduced, and after 17 h only
58% of 3 had been converted. However, still no influence on the enantioselectivity was observed (entry
9). More detailed results are given in Table 2.
Next we used our best ligand 2g in the alkylation of isobutyraldehyde 4 with diethylzinc, but
unexpectedly we obtained only the corresponding primary alcohol 13, which can be rationalized by
the pronounced steric hindrance of the carbonyl-C in 4. Finally, the four ligands 2a,b,f,g, which gave
the best results in the benzaldehyde series, were tested with hexanal 5 as the alkylation substrate, and
the better catalysts 2a,g yielded 3-octanol 11 with excellent chemical yield and good enantioselectivity
(Table 3). This is in good accordance with a recently published paper about the advantageous use of
morpholine as amino-partial structure in an aminoalcohol-ligand.24 Remarkably, aminoalcohol 2f gave
a higher enantiomeric excess for 3-octanol 11 compared to 1-phenylpropanol 10 which is quite unusual
(Table 3: entry 3 versus Table 2: entry 7) (cf. lit.,1 p. 1314).
In contrast to the arylalkylcarbinol 10 we were not able to get two baseline resolved signals for the
purely aliphatic alcohol 11 on our chiral stationary phase. Thus, we formed diastereomeric derivatives

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Table 2
Distribution of products and enantiomeric excesses of 1-phenyl-1-propanol 10 in the alkylation of
benzaldehyde 3 by diethylzinc catalyzed by one of the aminoalcohols 2a–g
Table 3
Distribution of products and enantiomeric excesses of 3-octanol 11 in the alkylation of hexanal 5 by
diethylzinc catalyzed by one of the aminoalcohols 2a,b,f,g

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of 11 by reaction with excessive anhydrolactol 1525 in the presence of p-toluenesulfonic acid to obtain
quantitatively acetals 16, which could be separated very easily by gas chromatography (Scheme 3).
Scheme 3. Acetal formation of 3-octanol 11 with the anhydrolactol 15 for determination of the enantiomeric excess of 11 by
GC
Comparing the selectivities achieved with different alkoxide counterions there is little which can be
generalized. In accordance with the literature,26 diethylzinc gives better results in the non-coordinating
solvent toluene than lithium- and Grignard-reagents in Et2O or THF. Whereas lithium organic compounds
(Table 1, entries 1 and 2) are more selective in ether solutions than in THF as solvent, no such dependence
is observed for Grignard-reagents (Table 1, entries 3 and 4), which may be attributed to different solvent
coordinating properties of the central metal. The question about ‘matched’ and ‘mis-matched’ pairs can
be asked for ligand 2f, which carries an additional stereogenic center derived from the amine component.
From the fact that there is no significant difference in the observed selectivities between 2f and the
average value of the other ligands when used with lithium and magnesium, it may be assumed that there is
almost no influence of this stereogenic chiral center. Nonetheless, it is worth mentioning that selectivities
obtained with 2f in Et2O are amongst the better ones, whereas in THF both lithium- as well as Grignard-
reagents are almost non-selective. In the case of diethylzinc 2f was significantly less selective than the
other ligands (with the exception of 2d). Therefore, the possibility that 2f represents the ‘mis-matched’
pair in this reaction should be considered.
In conclusion, we have shown that the camphor derived 1,4-aminoalcohols 2a–g on the one hand
exhibit only moderate chiral induction in the addition of n-BuLi and n-BuMgBr to benzaldehyde, but on
the other hand, seem to be promising ligands in the addition of organozinc reagents to aldehydes, which
will be further investigated.
3. Experimental
3.1. General
3.1.1. General procedure for the alkylation of benzaldehyde with n-BuLi and n-BuMgBr
To a solution of 5.2 mmol of the aminoalcohol 2a–g in 23 ml of anhydrous solvent (ether, THF) was
added 9.2 mmol of n-BuMgBr in 4 ml of ether (THF) with external cooling in a way that the temperature
of the reaction mixture did not exceed 10°C. In the case of the addition of n-BuLi 3.68 ml of n-BuLi
(9.2 mmol; 2.5 M solution in n-hexane) was added. After additional stirring at 0°C the mixture was
cooled to −78°C and a solution of 106 mg (1 mmol) of benzaldehyde in 2 ml of solvent was added. The
reaction mixture was stirred for 1 h at this temperature and quenched with 5 ml of H2O. The organic layer
was separated and the aqueous layer was extracted twice with ether. The combined organic layers were
extracted with 2N HCl, washed with water, dried with Na2SO4, filtered and the solvent was evaporated.
Yield: 79–100%, colorless oil, 1-phenyl-1-pentanol 9, Rf (PE:Et2O=3:1)=0.42. The ligands 2a–g could
be recovered quantitatively from the aqueous layer. Enantiomeric excess of 9 was determined directly

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by HPLC (column: Chiralcel OD (25 cm, 4.6 mm ID; Daicel Chemical Industries); conditions: flow: 1.7
ml/min; eluent: 0.7% 2-propanol and 2% t-butylmethylether in n-hexane. Rt: R(+)-1-phenyl-1-pentanol
15.70 min, (S)-(−)-1-phenyl-1-pentanol 17.70 min).
3.1.2. General procedure for the alkylation of benzaldehyde, isobutyraldehyde and hexanal with diethyl-
zinc
A 1.1 M solution of diethylzinc (2 ml, 2.2 mmol) in toluene was added dropwise at 0°C to an ice cooled
solution of one of the aldehydes 3–5 (1 mmol) and one of the aminoalcohols 2a–g in 6 ml of anhydrous
toluene. After stirring at rt for 17 h, the reaction was quenched by addition of 5 ml of 2N HCl, and the
aqueous layer was separated and extracted three times with 10 ml of diethylether. The combined organic
phases were washed with a saturated solution of NaHCO3, dried with sodium sulfate and concentrated
to give the crude product which was analyzed by GC (3, 10, 12: column: Carbowax 57 CB (25 m, 0.22
mm ID; Chrompack); conditions: pre-pressure 80 kPa, isotherm at 120°C. Rt: 3 for 14.79 min, 10 for
14.65 min, 12 for 15.06 min; 5, 11, 14: column: FS-LIPODEX-E (50 m, 0.25 mm ID; Macherey–Nagel);
conditions: pre-pressure 100 kPa, isotherm at 60°C. Rt: 5 for 13.10 min, 11 for 53.48 min, 14 for 27.78
min) to determine the product composition. Enantiomeric excess of 10 was determined directly by HPLC
(column: Chiralcel OD (25 cm, 4.6 mm ID; Daicel Chemical Industries); conditions: flow: 1.7 ml/min;
eluent: 0.7% 2-propanol and 2% t-butylmethylether in n-hexane. Rt: (R)-(+)-1-phenyl-1-propanol for
17.00 min, (S)-(−)-1-phenyl-1-propanol for 20.77 min). The enantiomeric purity of 11 was determined
after derivatization by GC analysis.
3.1.3. Procedure for derivative formation of 3-octanol 11 with anhydrolactol 15
The crude product (about 1 mmol) was treated with excessive anhydrolactol 15 (about 5 mmol) in
the presence of catalytic amounts of p-toluenesulfonic acid in dichloromethane for 1 h. The reaction
was stopped by addition of excessive sodium hydrogen carbonate, the solids were filtered off and the
solution was directly analyzed by GC (column: FS-LIPODEX-E (50 m, 0.25 mm ID; Macherey–Nagel);
conditions: pre-pressure 180 kPa, isotherm at 180°C. Rt: derivative of (R)-(+)-3-octanol for 17.21 min,
derivative of (S)-(−)-3-octanol for 19.10 min).
References
1. Houben–Weyl-Methods of Organic Chemistry; Helmchen, G.; Hoffmann, R. W.; Mulzer, J.; Schaumann, E., Eds.; Thieme:
Stuttgart, 1996; Vol. E21.
2. Nógrádi, M. Stereoselective Synthesis; VCH: Weinheim, 1995.
3. Noyori, R.; Kitamura, M. Angew. Chem. 1991, 103, 34.
4. Soai, K.; Niwa, S. Chem. Rev. 1992, 92, 833.
5. Blaser, H.-U. Chem. Rev. 1992, 92, 935.
6. Ager, D. J.; Prakash, I.; Schaad, D. R. Chem. Rev. 1996, 96, 835.
7. Cicchi, S.: Crea, S.; Goti, A.; Brandi, A. Tetrahedron: Asymmetry 1997, 8, 293.
8. Oppolzer, W.; Radinov, R. N. Tetrahedron Lett. 1988, 29, 5645.
9. Cho, B. T.; Kim, N. Tetrahedron Lett. 1994, 35, 4115.
10. Mellão, M. L.; Vasconcellos, M. L. A. A. Tetrahedron: Asymmetry 1996, 7, 1607.
11. Genov, M.; Kostova, K.; Dimitrov, V. Tetrahedron: Asymmetry 1997, 8, 1869.
12. Genov, M.; Dimitrov, V.; Ivanova, V. Tetrahedron: Asymmetry 1997, 8, 3703.
13. Knollmüller, M.; Ferencic, M.; Gärtner, P.; Mereiter, K.; Noe, C. R. Tetrahedron: Asymmetry 1998, 9, 4009.
14. Selected papers about the enantioselective addition reaction of organolithium compounds: (a) Mukaiyama, T.; Soai, K.;
Sato, T.; Shimizu, H.; Suzuki, K. J. Am. Chem. Soc. 1979, 101, 1455. (b) Mazaleyrat, J.-P.; Cram, D. J. J. Am. Chem. Soc.
1981, 103, 4585. (c) Eleveld, M. B.; Hogeveen, H. Tetrahedron Lett. 1984, 25, 5187. (d) Kanoh, S.; Muramoto, H.; Maeda,

M. Knollmüller et al. / Tetrahedron: Asymmetry 10 (1999) 3969–3975
3975
K.; Kawaguchi, N.; Motoi, M.; Suda, H. Bull. Chem. Soc. Jpn. 1988, 61, 2244. (e) Ye, M.; Logaraj, S.; Jackman, L. M.;
Hillegass, K.; Hirsch, K. A.; Bollinger, A. M.; Grosz, A. L.; Mani, V. Tetrahedron 1994, 50, 6109. (f) Huffman, M. A.;
Yasuda, N.; DeCamp, A. E.; Grabowski, E. J. J. J. Org. Chem. 1995, 60, 1590. (g) Basu, A.; Beak, P. J. Am. Chem. Soc.
1996, 118, 1575. (h) Thompson, A.; Corley, E. G.; Huntington, M. F.; Grabowski, E. J. J.; Remenar, J. F.; Collum, D. B. J.
Am. Chem. Soc. 1998, 120, 2028. (i) Corruble A.; Valnot J.-Y.; Maddaluno, J.; Duhamel, P. J. Org. Chem. 1998, 63, 8266.
15. Selected papers about the enantioselective addition reaction of Grignard compounds: (a) Seebach, D.; Beck, A. K.; Roggo,
S.; Wonnacott, A. Chem. Ber. 1985, 118, 3673. (b) Tomioka, K.; Nakajima, M.; Koga, K. Chem. Lett. 1987, 65. (c) Weber,
B.; Seebach, D. Angew. Chem. 1992, 104, 96; Angew. Chem., Int. Ed. Engl. 1992, 31, 84.
16. Schön, M.; Naef, R. Tetrahedron: Asymmetry 1999, 10, 169.
17. Weber, B.; Seebach, D. Tetrahedron 1994, 50, 6117.
18. Knollmüller, M.; Gärtner. P.; Letschnig, M. Monatsh. Chem. 1998, 129, 953.
19. For reviews, see: (a) Ref. 3; (b) Ref. 4; (c) Noyori, R. Asymmetric Catalysis in Organic Synthesis; John Wiley & Sons:
New York, 1994; Chapter 5.
20. Cho, B. T.; Chun, Y. S. Tetrahedron: Asymmetry 1998, 9, 1489.
21. Cho, B. T.; Kim, N. J. Chem. Soc., Perkin Trans. 1 1996, 2901.
22. Soai, K.; Yokoyama, S.; Hayasaka, T. J. Org. Chem. 1991, 56, 4264.
23. Soai, K.; Ookawa, A.; Kaba, T.; Ogawa, K. J. Am. Chem. Soc. 1987, 109, 7111.
24. Nugent, W. A. Chem. Commun. 1999, 1369.
25. Noe, C. R.; Knollmüller, M.; Gärtner, P.; Mereiter, K.; Steinbauer, G. Liebigs Ann. 1996, 1015.
26. For an excellent review, see: Evans, D. A. Science (Washington, DC) 1988, 240, 420.